Atrial fibrillation (AF) is the most common heart rhythm disorder and affects 2.3 million Americans, accounting for frequent health care utilization, increased hospitalizations and increased risks of stroke, heart failure and mortality. Evidence suggests that ectopic beats from the pulmonary veins may trigger AF, a finding that has led to development of the non-pharmacological therapy called pulmonary vein (PV) isolation, which uses radiofrequency energy to cauterize the atrial tissue in the PV's atrium in order to terminate AF and restore sinus rhythm. Unfortunately, this therapy remains suboptimal, with long-term success rates of only 40% to 60%. The main reason for such unsuccessful outcomes is that it fails to eliminate AF drivers outside the pulmonary veins (PVs), and their targeted elimination is key to improving outcomes after AF ablation. Sustained rotor-like activities (RotAs) outside PVs have been shown to be relevant to the sustaining mechanism and perpetuation of AF and should be targeted for AF ablation. However, there is no well-defined algorithm for localization of RotAs using a conventional Multi-Polar Diagnostic Catheter (MPDC). Thus, the development of such an algorithm will play a significant role in the successful detection and ablation of AF drivers outside the PVs and in increasing the success of AF termination procedures. Our objective in this project is to dramatically improve detection of RotAs by combining MPDC with a mathematical, model-based catheter-guidance algorithm to locate RotAs. Based on our preliminary observations of RotAs in human AF, it is expected that using a catheter-guidance algorithm, as will be developed in the proposed study, will significantly increase successful localization of RotAs. Our research will proceed according to the following specific aims: (1) Develop a library of simulated AF datasets with RotAs and (2) Design a catheter-guidance algorithm to direct an MPDC towards RotAs. We will develop a novel catheter-guidance algorithm and validate its performance through simulation of clinically-oriented variations such as noise, poor contact, and cardiac motion, as well as complex models of cardiac cellular electrophysiology, atrial geometry remodeling, and fibrosis. Clinically, the proposed interdisciplinary collaboration should develop a novel, low-risk and low-cost algorithm add-on allowing improved and patient-specific localization of AF perpetuation sites, which cannot currently be achieved. This would significantly improve the success of AF ablation at first attempt and facilitate treating patients before progression of AF to the permanent stage. It would also significantly reduce the unnecessary ablation sites that destroy healthy endocardium and may result in future complications for patients, and thus enhance the health of millions of patients afflicted by this debilitating rhythm disorder so that they can live longer and more fulfilling lives.